Postgrad Med J: first published as 10.1136/pgmj.46.535.314 on 1 May 1970. Downloaded from Pcstgraduate Medical Journal (May 1970) 46, 314-317. CURRENT SURVEY Hypnotic drugs RUSSELL R. MILLER* DIRK V. DEYOUNG Pharm. D. M.D. Director, Drug Communications Study, Assistant Medical Director, University of Chicago Continental Assurance Company, Chicago JAMES PAXINOS B.S (Pharm.) Assistant Director for Clinical Services, Department ofPharmacy, University of Chicago Hospitals and Clinics THIS review will treat the more commonly prescribed Human pharmacology hypnotic agents and their sleep-inducing properties. In the past, hypnotics have been divided into Hypnotic agents that are seldom used (paraldehyde), barbiturates and non-barbiturates. This classification, drugs that are not singularly soporific but may be based on chemical structure, has little contemporary used either alone or as adjuncts in inducing sleep [e.g. clinical significance since compounds in each group meprobamate (Equanil, Miltown), chlordiazepoxide have essentially the same qualitative pharmacologic (Librium) and diazepam (Valium)] and drugs that properties. Naturally, there are quantitative differ- copyright. have little soporific effect [antihistamines, bromides ences in onset and duration of action. and methylparafynol (Oblivon, Dormison) (Lasagna, 1954)] will not be discussed. Onset of action Indications Onset is generally rapid with liquid preparations Insomnia is an extremely common complaint with such as syrup of chloral hydrate (Noctec, Somnos), which are confronted. elixir of pentobarbital (Nembutal) and elixir of physicians perpetually Many not as patients have chronic insomnia. In other patients secobarbital (Seconal). However, liquids are http://pmj.bmj.com/ insomnia is acute but intermittent. Situations in convenient as capsules and since a capsule of sodium which acute insomnia can occur are during or after secobarbital, sodium pentobarbital or chloral plane or train travel, hospitalization in strange and hydrate usually causes drowsiness within about often noisy surroundings or simply having to sleep 30 min, these three compounds give quite satis- in environments that are different or unfamiliar. factory hypnotic results in most patients in capsular There appear to be three basic types of insomnia. form. In one a has in Onset of action is also related to the intrinsic type person difficulty only falling on September 29, 2021 by guest. Protected asleep. In a second type, individuals achieve sleep pharmacodynamic nature of the particular hypnotic easily, but have trouble staying asleep. In a third agent. An 'ultra-short acting' barbiturate such as type, both falling and remaining asleep are physiolo- hexobarbital (Sombulex, Cyclonal) probably has the gically arduous. most prompt onset of action while a 'long-acting' Let us emphasize that chronic insomnia is best barbiturate such as phenobarbital may require treated by attacking the underlying cause, ifapparent. several hours to produce maximal effect (Sharpless, If not evident, the cause (or causes) should be care- 1965a). The reasons for the variability of pharmaco- fully sought by the physician. Lack of sleep associ- dynamic (and thus biochemical) behaviour among ated with somatic pain or with a psychiatric problem, the various hypnotic agents is beyond the scope of for example, may be treated best by prescribing this review (see Shideman, 1961; Sharpless, 1965a, b). analgesics, or tranquilizers and/or psychotherapy. * Postdoctoral Fellow, National Library of Medicine, Duration of action U.S. Department of Health Education and Welfare. Duration of effect is Requests for reprints should be addressed to Dr Miller, hypnotic largely dependent Box 96, University ofChicago Hospitals and Clinics, Chicago, on two factors, the intrinsic pharmacodynamic Illinois 60637, U.S.A. characteristics of the drug and the dosage used. Postgrad Med J: first published as 10.1136/pgmj.46.535.314 on 1 May 1970. Downloaded from Current survey 315 Both of these factors should be considered when in some persons following administration of a selecting a hypnotic agent. If a patient requires a barbiturate. However, such an effect appears to be drug with a rapid but brief hypnotic effect, perhaps a rather rare phenomenon. It is said to occur less one of the 'ultra-short acting' barbiturates, ordinarily frequently with chloral hydrate than with the barbi- used as intravenous anaesthetics, may be useful. turates. Similarly, the alleged capacity of hypnotics Bush, Berry & Hume (1966) studied oral sodium to produce delirium in patients with pain is rarely hexobarbital (Sombulex, Cyclonal), sodium metho- evident clinically. There seems to be little reason to hexital and sodiumthiopental(nooral preparationsof avoid prescribing hypnotics for patients in pain who the latter two drugs are commercially available) and also have insomnia. Of course, appropriate anal- their results indicate that thesethreedrugs maybe use- gesics should also be prescribed. ful in treatment ofpatients who have difficulty in fall- Gastric irritation is said to be a problem with ingasleep but who, once asleep, do not easily awaken. chloral hydrate but modem dosage forms (capsules, If a patient needs a hypnotic for both inducing syrup) appear to have largely eliminated this side and maintaining sleep, one of the longer acting effect. Chloral betaine (Beta-Chlor), a relative of hypnotics in an appropriate dose is indicated. In most chloral hydrate, is said to cause less gastric irrita- patients a 1-0 g dose of chloral hydrate, for example, tion but there is no objective evidence to support will provide adequate sleep but doses of 1-5 g or this claim. 2-0 g may be necessary in some patients. Hangover, or residual sedation after waking, is a The older designations of hypnotics as being problem with many of the hypnotics although in 'short-acting', 'medium-acting', 'long-acting', are some patients, e.g. certain hospitalized persons, this clinically and pharmacodynamically meaningless. effect may not be undesirable. The only hypnotics Such labels have no scientific meaning because there not having this side-effect are the 'ultra-short acting' are no valid human data to support them. No con- barbiturate hexobarbital (Sombulex, Cyclonal) and, trolled human studies have been done, showing that for most persons, the non-barbiturate compound specified doses of several hypnotics have different ethinamate (Valmid). Other barbiturates, although durations of action. Thus, commercial preparations called 'short-acting', are all known to have this side combining a 'short-acting' barbiturate with a effect. The non-barbiturates methyprylon (Noludar), copyright. 'moderately long-acting' barbiturate (as in Tuinal) ethchlorvynol (Arvynol, Serenesil, Placidyl), meth- are not pharmacologically rational. By increasing or aqualone (Quaalude, Melsed, Melsedin, Paxidorm) decreasing the dosage of such a drug as secobar- and glutethimide (Doriden), have this side-effect in bital, for instance, the physician can usually obtain some persons, also; there are no well-designed any effect from relatively brief and shallow sedation studies demonstrating their lack of hangover. With to a prolonged and rather profound coma-like state. all hypnotics hangover can be minimized by titrating each patient's insomnia against different doses of a Dose variability particular drug. http://pmj.bmj.com/ The dose required for a satisfactory hypnotic Various allergic reactions have been noted with effect varies greatly among individual patients. Such the use of all hypnotics. The symptoms usually are variability can be explained in part by individual skin rash, pruritus, nausea and vomiting. differences in the metabolism of a drug or in the More serious adverse effects have been en- response of individual central nervous systems to a countered. The Registry on Adverse Reactions of the given concentration of the drug. But the necessary American Medical Association has received a num- dose is also related to other differences in a patient's ber of reports of reactions to hypnotic drugs (see condition, such as the degree of anxiety or depres- Table 1). A direct causal relationship was not de- on September 29, 2021 by guest. Protected sion present, and to the environment in which he finitely established because these reports come from a must sleep. Thus, the use of a 'standard' dose under variety of sources not subject to follow-up investiga- all circumstances is not rational (or efficacious) tion. The reports may represent only a fraction of therapeutics. A patient should first receive a rela- the reactions which do occur. tively low dose of a hypnotic (e.g. 0-5 g of chloral In addition to the unpublished Registry reports, hydrate or 50 mg of secobarbital or pentobarbital). adverse reactions have also been reported in the If hypnosis is not achieved, the dose may be doubled literature. Two cases of peripheral neuropathy due or even tripled. It is generally better therapeutics to to glutethimide werereportedbyBartholomew (1961). adjust the dose of a specific drug with which the Cases of thrombocytopenia following the use of physician is familiar to the individual requirements ethinamate have been reported (Sharpless, 1965b). of the patient than to try other drugs. Methaqualone has been cited as a possible cause of aplastic anaemia (New Drugs, 1967). Side-effects Acute intoxication or poisoning with the hypnotics Paradoxical mental excitement reportedly occurs is common. It has been estimated that there are Postgrad